Pyrrolo[1,4]benzodiazepine dimers are anticancer agents that act by covalently binding to cellular DNA. These derivatives have been described in patent applications WO 00/12508 and WO 2005/085260 and also in the following publications: Eur. J. Med. Chem. 2005, 40, 641-654; Tetrahedron Letters 1988, 29(40), 5105-5108.
Conjugates chemistry has been known for many years and has been applied to several families of cytotoxic agents, for instance maytansinoids (WO 04103272), taxanes (WO 06061258), leptomycins (WO 07144709), CC-1065 and analogues thereof (WO 2007102069); with regard to conjugates, see also Monneret C. et al., Bulletin du Cancer 2000, 87(11), 829-38; Ricart A. D. et al., Nature Clinical Practice Oncology 2007, 4, 245-255; Singh R. and Rickson H. K., Therapeutic Antibodies: Methods and Protocols, 2009, 525, 445-467.
Conjugates of pyrrolo[1,4]benzodiazepine dimers have been described in patent applications WO 07085930 and WO 2009/016516. The dimers used have the formulae:
in which T may represent an aryl or heteroaryl group substituted with -G-D-(Z)p—SZa or -G-D-(Z)p— C(═O)ZbRb. G represents a single or double bond or alternatively —O—, —S— or —NR—. D represents a single bond or one of the following groups: -E-, -E-NR—, -E-NR—F—, -E-O—, -E-O—F—, -E-NR—CO—, -E-NR—CO—F—, -E-CO—, —CO-E-, -E-CO—F, -E-S—, -E-S—F—, -E-NR—C—S—, -E-NR—CS—F— for which E and F are chosen from —(OCH2CH2)ialkyl(OCH2CH2)j—, -alkyl(OCH2CH2)i-alkyl, —(OCH2CH2)i, —(OCH2CH2)icycloalkyl(OCH2CH2)j—, —(OCH2CH2)iheterocyclyl-(OCH2CH2)j—, —(OCH2CH2)iaryl(OCH2CH2)j—, —(OCH2CH2)iheteroaryl(OCH2CH2)j—, -alkyl-(OCH2CH2)ialkyl(OCH2CH2)j—, -alkyl-(OCH2CH2)i—, -alkyl-(OCH2CH2)icycloalkyl-(OCH2CH2)j—, -alkyl(OCH2CH2)iheterocyclyl(OCH2CH2)j—, -alkyl-(OCH2CH2)iaryl-(OCH2CH2)j—, -alkyl(OCH2CH2)iheteroaryl(OCH2CH2)j—, -cycloalkyl-alkyl-, -alkyl-cycloalkyl-, -heterocyclyl-alkyl-, -alkyl-heterocyclyl-, -alkyl-aryl-, -aryl-alkyl-, -alkyl-heteroaryl-, -heteroaryl-alkyl-. i and j represent integers ranging from 0 to 2000. Z represents an alkyl group and p is an integer equal to 0 or 1. In these compounds, the R of the group NR does not comprise a PEG chain.
Immunogen described in November 2009 at the EORTC Congress (Abstract B-126) the following conjugate:
which is distinguished by the nature of the linker and of the cytotoxic compound. This compound was redescribed at the Sixth Annual PEGS Congress in Boston which took place on 17 to 21 May 2010, and also the following precursors:
with R=N-succinimidyl or methyl.
The following dimers are especially described, respectively, in WO 07085930 and WO 2009/016516:

These three applications do not describe or suggest the novel linkers of the invention, which comprise one or two pegylated chains.